Pimecrolimus is an anti-inflammatory compound derived from the macrolactam natural product ascomycin, produced by certain strains of Streptomyces. 

Pimecrolimus is sold in the United States under the brand name ELIDEL®, and is approved for use against atopic dermatitis. The systematic name of pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21 S,23S,24R,25S,27R)-12-[(1E)-2-{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone. Pimecrolimus is the 32 epichloro derivative of ascomycin. Its empirical formula is C43H68ClNO11, and its molecular weight is 810.47.
Many pharmaceutical solids can exist in different physical forms. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystalline lattice. Amorphous solids consist of disordered arrangements of molecules, and do not possess a distinguishable crystal lattice.
Polymorphs of a pharmaceutical solid may have different physical and solid-state chemical (reactivity) properties. These polymorphs differ in internal solid state structure, and, therefore, possess different chemical and physical properties, including packing, thermodynamic, spectroscopic, kinetic, interfacial, and mechanical properties. These properties can have a direct impact on drug product quality/performance, including stability, dissolution, and bioavailability.
The most stable polymorphic form of a drug substance is often used in a formulation because it has the lowest potential for conversion from one polymorphic form to another. On the other hand, metastable (a form other than the most stable form) and even amorphous forms may be chosen to enhance the bioavailability of the drug product. An amorphous form, being a disorganized solid mass, does not need to lose crystal structure before dissolution in the gastric juices, and, thus, often has greater bioavailability than a crystalline form.
Even if an amorphous form is desirable for formulation, its preparation on industrial scale is often problematic. Many processes used to prepare the amorphous form of an active pharmaceutical ingredient are not suitable for industrial scale production. In POLYMORPHISM IN PHARMACEUTICAL SCIENCES, DRUGS AND THE PHARMACEUTICAL SCIENCES, Vol. 95, the authors survey various processes for preparation of amorphous forms, and list solidification of melt, reduction of particle size, spray-drying, lyophilization, removal of a solvent from crystalline structure, precipitation of acids and bases by change in pH, and others such techniques employed to obtain the amorphous form of an active pharmaceutical ingredient.
Many of these processes however are not practical on an industrial scale. For example, to obtain an amorphous active pharmaceutical ingredient by solidification of melt, the active pharmaceutical ingredient has to be heated beyond its melting point, which may require expenditure of much energy, particularly when the active pharmaceutical ingredient has a high melting point. Further, the high temperatures may chemically damage the active pharmaceutical ingredient.
Another one of these processes, lyophilization, is quite expensive on large scale, and generally has limited capacity. Furthermore, lyophilization with an organic solvent is often dangerous since it presents a fire hazard.
According to Remington: THE SCIENCE AND PRACTICE OF PHARMACY, 19th Ed., vol. II, pg. 1627, spray-drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. Spray-drying however is often limited to aqueous solutions unless special expensive safety measures are taken. Also, in spite of the short contact time, certain undesirable physical and chemical characteristics of the emerging solids are in particular cases unavoidable. The turbulence present in a spray-drier as a result of the moving air may alter the product in an undesirable manner. Modifications to the spray-drying technique are disclosed in WO 03/063821 and WO 03/063822.
European Patent EP 427 680 B1 discloses a method of synthesizing amorphous pimecrolimus (Example 66a). The method yields amorphous pimecrolimus as a colorless foamy resin.
U.S. Pat. No. 6,423,722 discloses crystalline forms of pimecrolimus, such as form A, form B, etc. U.S. '722 also contend that by performing example 66a from the European Patent EP 427 680 B 1, amorphous pimecrolimus is obtained.
However, there is a need for methods of preparing amorphous pimecrolimus that is characterized as non-hygroscopic and/or powdery. There is also a need for methods of preparing such amorphous pimecrolimus preferably using techniques and equipment suitable for industrial scale preparation. The present invention provides such methods.